Benzothioxepanone and benzothioxepane thione compounds

ABSTRACT

Novel benzothioxepanone and benzothioxepane thione compounds are characterized by the formula   &lt;IMAGE&gt;   wherein Z is:    &lt;IMAGE&gt;  [1]   &lt;IMAGE&gt;  [2]  R is Cl, Br, F, C1 to C8 alkyl, or C1 to C8 alkoxy; X and Y are each hydrogen, or taken together form a fused cyclopentyl or cyclohexyl ring, with the proviso that when Z is [1], X and Y represent a fused cyclopentyl or cyclohexyl ring; and n is 0, 1, or 2. The compounds are useful as co-catalysts in the para-directed nuclear chlorination of toluene.

This application is a division of application Ser. No. 08/763,449, filedDec. 2, 1996, now U.S. Pat. No. 5,714,603, granted Feb. 3, 1998, whichis a division of Ser. No. 08/426,208, filed Apr. 21, 1995, now U.S. Pat.No. 5,621,153, granted Apr. 15, 1997.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to a catalyzed process for the para-directed ringchlorination of alkylbenzenes and to novel compounds useful ascatalysts. The para-alkylbenzenes, such as para-chlorotoluene, areuseful as chemical intermediates for the synthesis of various chemicalproducts, especially agricultural chemical and pharmaceutical products.

2. Prior Art

The production of nuclear chlorinated alkylbenzenes, such asmono-chlorotoluene, is well-known and of considerable commercialimportance. Typical commercial processes involve the chlorination of analkylbenzene, such as toluene, in the presence of a chlorinationcatalyst, such as ferric chloride, antimony chloride, aluminum chloride,and the like. The usual product of such reactions is a mixture ofvarious monochlorinated and/or polychlorinated compounds. For example,in the liquid phase substitution-chlorination chlorination of toluene byreaction of chlorine and toluene, to form monochlorotoluene, the usualproduct is a mixture of orthochlorotoluene and para-chlorotoluene, whichmay, in addition, contain varying amounts of other chlorinated productssuch as meta-chlorotoluene, dichlorotoluenes, various polychlorotoluenesand benzylic chlorides.

In the ring chlorination of toluene, since there are two ortho sites andonly one para site where substitution may occur, the production oforthochlorotoluene is favored. Because of the greater commercial valueof parachlorotoluene, considerable effort has been expended in attemptsto direct the chlorination reaction in such a manner as to lower theratio of orthochlorotoluene to parachlorotoluene, that is, to discoverreaction conditions under which the formation of parachlorotoluene isfavored.

U.S. Pat. No. 1,946,040 discloses that when alkylbenzenes are reactedwith chlorine, the yield of parachlorinated product is improved with theaid of a mixed catalyst comprising sulfur and antimony trichloride and,optionally, iron or lead.

In British Patent No. 1,153,746 (1969) it is disclosed that in thechlorination of toluene in the presence of a ring chlorination catalyst,such as ferric chloride, antimony chloride, and the like, the ratio oforthochloro to parachloro isomers produced may be lowered by thepresence of an organic sulfur compound such as thiophene,hexadecylmercaptan, dibenzothiophene or the like.

British Patent No. 1,163,927 (1969) discloses that the formation ofparachlorotoluene is enhanced when toluene is reacted with chlorine inthe presence of elemental sulfur, or an inorganic sulfur compound, and aring chlorination catalyst, such as ferric chloride, aluminum chloride,antimony chloride, zinc chloride, iodine, molybdenum chloride, stannouschloride, zirconium chloride, or boron trifluoride.

U.S. Pat. No. 3,226,447 (1965) teaches that in thesubstitution-chlorination of benzene and toluene, the ratio of orthoisomer to paraisomer in the mono-chlorinated product may be lowered whenthe reaction is carried out in the presence of an iron, aluminum orantimony halide catalyst and a co-catalyst which is an organic sulfurcompound wherein the sulfur is divalent. Examples of such co-catalystinclude various mercaptans, mercapto-aliphatic carboxylic acids,aliphatic thiocarboxylic acids, alkyl sulfides, alkyl disulfides,thiophenols, aryl sulfides, aryl disulfides and the like containingdivalent sulfur.

According to U.S. Pat. No. 3,317,617 (1967) the formation ofparachlorotoluene is favored when toluene is reacted with chlorine inthe presence of platinum dioxide.

U.S. Pat. No. 4,031,144 (1977) discloses that a mono-chlorotolueneproduct having an unusually high para-chlorotoluene content is obtainedwhen toluene is chlorinated in the presence of a catalyst system thatcontains a ferrocene compound and a co-catalyst that is sulfur or acompound that contains at least one divalent sulfur atom, such assulfur, sulfur monochloride, sulfur dichloride carbon disulfide,thiophenes, thiophanes, alkylcycloalkyl-, aryl- and aralkyl mercaptansand dimercaptans, thioethers, and the like.

U.S. Pat. No. 4,013,730 (1977) discloses a process for the preparationof monochlorotoluene having a reduced orthochloro- to parachloro isomercontent which comprises reacting toluene with chlorine in the presenceof a catalyst system comprising a Lewis acid catalyst and, as aco-catalyst, diphenyl selenide or aluminum selenide.

Still further improvements in the preparation of monochlorotoluenehaving a low ortho to para isomer ratio are disclosed in U.S. Pat. Nos.4,031,142 and 4,031,147 (1977). U.S. Pat. No. 4,031,142 discloses aprocess for the preparation of nuclear chlorinated alkylbenzenes, suchas monochlorotoluene which comprises reacting an alkylbenzene, such astoluene, with chlorine in the presence of a Lewis acid catalyst and, asa co-catalyst, thianthrene. In accordance with U.S. Pat. No. 4,031,147,even lower ratios of ortho to para isomer are obtained inmonochloroalkylbenzene products prepared by the reaction of analkylbenzene with chlorine in the presence of a Lewis acid catalyst anda thianthrene compound having electron-withdrawing substituents, such aschlorine, present at the 2,3,7 and/or 8 position of the thianthrenenucleus.

U.S. Pat. Nos. 4,069,263 and 4,069,264 disclose processes for thedirected nuclear chlorination of alkylbenzenes wherein an alkylbenzene,such as toluene is reacted with chlorine in the presence of asubstituted thianthrene having both electron-withdrawing substituentsand electron-donating substituents on the nucleus thereof.

U.S. Patent 4,250,122 (1981) to Lin discloses a process for thepara-directed chlorination of toluene by reaction with chlorine in thepresence of a catalyst mixture prepared by (a) reacting sulfurmonochloride with toluene or chlorotoluene in the presence of a Lewisacid catalyst and (b) reacting the reaction product of (a) withchlorine.

U.S. Pat. No. 4,289,916 (1981) to Nakayama et al. teaches a process forproducing p-chloroalkylbenzene selectively by chlorinating analkylbenzene in the presence of a phenoxathiin compound.

U.S. Pat. No. 4,647,709 (1987) to Wolfram discloses a high proportion ofp-chlorotoluene is obtained when toluene is chlorinated in the presenceof a Lewis acid catalyst and a co-catalyst comprising a chlorinationproduct of 2,8,-dimethylphenoxathiin. The primary component of theco-catalyst is 1,3,7,9-tetrachloro-2,8-dimethylphenoxathiin.

U.S. Pat. No. 4,851,596 (1989) to Mais et al. discloses the ringchlorination of alkylbenzenes in the presence of Friedel-Craftscatalysts and thiazepine compounds as co-catalysts.

U.S. Pat. No. 4,925,994 (1990) to Mais discloses an increase in theproportion of p-chloroalkylbenzenes when alkylbenzenes are chlorinatedin the presence of a Friedel-Crafts catalyst and a 1,6-benzothiazocinco-catalyst.

U.S. Pat. No. 4,990,707 (1991) to Mais et al. discloses the nuclearchlorination of alkylbenzenes in the presence of a Friedel-Craftscatalyst and, as a co-catalyst, a benzo-fused imine or benzof!-1,4-thiazepine compound to increase the proportional yield ofparachloroalkylbenzenes.

U.S. Pat. No. 5,105,036 (1992) to Mais et al. discloses a process forthe nuclear chlorination of alkylbenzenes in the presence ofFriedel-Crafts catalysts and a co-catalyst which is a cyclic amidinethat is oxy-substituted on the exocyclic N atom. The process results ina reaction product containing an increased proportion of the p-chloroisomer.

SUMMARY OF THE INVENTION

In accordance with the present invention, there is provided a processfor the production of nuclear chlorinated alkylbenzenes which comprisereacting an alkylbenzene of the formula: ##STR3## where Alkyl is analkyl or cycloalkyl radical of up to 12 carbon atoms with a chlorinatingagent in the presence of a Lewis acid catalyst and a cocatalystcomprising a compound or mixture of compounds characterized by theformula: ##STR4## wherein Z is: ##STR5## R is Cl, Br, F, C₁ to C₈ alkyl,or C₁ to C₈ alkoxy; x and y are each hydrogen, or taken together form afused cyclopentyl or cyclohexyl ring; n is 0, 1, or 2, with the provisothat when Z is 3!, n is 0 or 1. The preferred co-catalysts are thosewherein R is C₁ -C₄ alkyl, most preferably methyl, n is 0 or 1, and Xand Y together form a fused cyclopentyl or cyclohexyl ring.

In a second aspect, the present invention comprises a group of novelcompounds, useful as catalysts. The novel compounds of this inventionare characterized by the formula: ##STR6## wherein Z is: R is Cl, Br, F,C₁ to C₈ alkyl, or C₁ to C₈ alkoxy; X and Y are each hydrogen, or takentogether form a fused cyclopentyl or cyclohexyl ring, with the provisothat when Z is 1!, X and Y represent a fused cyclopentyl or cyclohexylring; n is 0, 1, or 2, with the proviso that when Z is 3!, n is 0 or 1.

DETAILED DESCRIPTION OF THE INVENTION

A wide variety of Lewis acid catalysts may be employed in the process ofthe present invention. The term "Lewis acid catalyst" as employed hereinincludes, in addition to Lewis acids, those compounds or elements thatwill form Lewis acids under the conditions of the chlorination reaction.Preferred catalysts for this purpose are compounds of antimony, lead,iron, molybdenum and aluminum, including for example, the halides,oxyhalides, oxides, sulfides, sulfates, carbonyls and elemental form ofthese elements and mixtures of such compounds and most preferably thechlorides of aluminum, antimony, and iron. Typical of the catalystswhich may be employed in the process of this invention are aluminumchloride, antimony trichloride, antimony pentachloride, antimonytrioxide, antimony tetraoxide, antimony pentaoxide, antimonytrifluoride, antimony oxychloride, molybdenum hexacarbonyl, leadsulfide, ferric chloride, ferrous chloride, ferrous sulfate, ferricoxide, ferrous sulfide, iron disulfide, iron pentacarbonyl, iron metal,and the like.

The preferred co-catalysts which may be employed in the chlorinationprocess of this invention include compounds of the structures: ##STR7##wherein X and Y together form a fused cyclopentyl or cyclohexyl ring,and n is 0 or 1. When n is 1, R is preferably C₁ -C₄ alkyl, and mostpreferably methyl.

    __________________________________________________________________________    CO-CATALYSTS OF THIS INVENTION                                                Compound No.                                                                         Structure and Name                                                     __________________________________________________________________________            ##STR8##            (See Examples 1-6)                                       2,3-Dihydro-2,3-tetramethylene-1,5-benzo-1,4-thioxepan-5-one           2                                                                                     ##STR9##            (See Example 7)                                          2,3-Dihydro-2,3-tetramethylene-1,5-benzo-1,4-thioxepan-5-thione        3                                                                                     ##STR10##           (See Example 8)                                          2,3-Dihydro-2,3-trimethylene-1,5-benzo-1,4-thioxepan-5-one             4                                                                                     ##STR11##           (See Example 9)                                          8-Chloro-2,3-dihydro-2,3-tetramethylene-1,5-benzo-1,4-thioxepan-5-o           ne                                                                     5                                                                                     ##STR12##           (See Example 10)                                         2,3-Dihydro-1,5-benzothioxepan-5-one                                   6                                                                                     ##STR13##           (See Example 11)                                         7-Methyl-2,3-dihydro-2,3-tetramethylene-1,5-benzo-1,4-thioxepan-5-o           ne                                                                     7                                                                                     ##STR14##           (See Example 12)                                         7,8-Dimethoxy-2,3-dihydro-2,3-tetramethylene-1,5-benzo-1,4-thioxepa           n-5-one                                                                8                                                                                     ##STR15##           (See Example 13)                                         9-Methyl-2,3-dihydro-2,3-tetramethylene-1,5-benzo-1,4-thioxepan-5-o           ne                                                                     9                                                                                     ##STR16##           (See Examples 14-17)                                     2,3-Dihydro-2,3-tetramethylene-1,6-benzo-1,4,6-thioxazocin-5(6H)-on           e                                                                      10                                                                                    ##STR17##           (See Example 18)                                         8-Methyl-2,3-dihydro-2,3-tetramethylene-1,6-benzo-1,4,6-thioxazocin           -5(6H)-one                                                             11                                                                                    ##STR18##           (See Example 19)                                         10-Methyl-2,3-dihydro-2,3-tetramethylene-1,6-benzo-1,4,6-thioxazoci           n-5(6H)-one                                                            12                                                                                    ##STR19##           (See Example 20)                                         8-Chloro-2,3-dihydro-2,3-tetramethylene-1,6-benzo-1,4,6-thioxazocin           -5(6H)-one                                                             __________________________________________________________________________

The process of the invention is typically carried out in the liquidphase with the alkylbenzene reactant serving as solvent or primaryliquid reaction medium. If desired, the reaction mixture may be dilutedby addition of an inert solvent. Suitable solvents are those inert tothe reactants and conditions of the process of the invention, such asmethylene chloride, chloroform, and carbon tetrachloride. Preferably,the process is carried out without addition of an inert solvent.

The amounts of catalyst and co-catalyst employed may vary considerably.Substantial benefits in terms of the lowering of the ratio of ortho- topara- isomer in the product may be achieved, for example, when theco-catalyst is present in an amount sufficient to provide a molar ratioof alkylbenzene:co-catalyst ranging from less than about 500:1 to60,000:1 or higher. The preferred alkylbenzene:co-catalyst molar ratiois between about 30,000:1 and 50,000:1.

The amounts of catalyst and co-catalyst are typically sufficient toprovide a molar ratio of catalyst:co-catalyst of between about 0.01:1and 20:1, preferably between about 0.0:1 and 10:1.

Although it is preferred to carry out the process at atmosphericpressure, sub-atmospheric or superatmospheric pressures may be employed,if desired.

Under atmospheric pressure, the chlorination of alkylbenzenes, inaccordance with the present invention, may be carried out over a widerange of temperatures, ranging for example from sub-zero temperaturessuch as -30° C. or below to over 100° C. The upper limit of temperatureis, of course, determined by the boiling point of the reaction medium,and may, depending on the boiling point limitation, range as high as150° C. or higher. However, no practical advantage is gained through theuse of higher temperatures or extremely low temperatures and it ispreferred to employ temperatures in the range of about 20° to 100° C.and preferably about 40° to 60° C. The optimum temperature will varysomewhat, depending on the particular alkylbenzene and catalyst systememployed.

The following specific examples are provided to further illustrate thisinvention and the manner in which it may be practiced.

Examples 1-6

In a glass reactor wrapped in aluminum foil, a mixture of 70.4 g (0.764mole) of toluene, 0.0062 g (3.8×10⁻⁵ mole) FeCl₃, and 0.0045 g(1.911×10⁻⁵ mole) of2,3-dihydro-2,3-tetramethylene-1,5-benzo-1,4-thioxepan-5-one (Formula 1)was heated to 50° C., in a nitrogen atmosphere, and maintained thereat,with stirring, while chlorine gas was passed through the reactor atabout 70 SCCM over a period of 3.25 hours. The course of the reactionwas monitored using gas chromatography to follow the disappearance oftoluene. When 90% of the toluene had reacted, chlorine addition wasstopped and the apparatus was swept with nitrogen and cooled to roomtemperature. Gas chromatographic analysis of the reaction mixtureindicated a 93% yield of monochlorotoluene with an o/p of 0.85.

The general procedure of Example 1 was repeated using the samereactants, catalyst and co-catalyst, varying the amounts and conditionsand with the results as shown in Table 1 below.

                                      TABLE 1                                     __________________________________________________________________________          Tol/ FeCl.sub.3                                                         T     Cocat                                                                              Cocat   Wt of Reagents (g)                                                                       Cl.sub.2                                        EX °C.                                                                       M.R..sup.a                                                                         M.R..sup.a                                                                        o/p PhMe                                                                             FeCl.sub.3                                                                        Cocat                                                                             SCCM                                                                              Time                                        __________________________________________________________________________    1  50 40000                                                                              2.0  0.8500                                                                           70.4                                                                             0.0062                                                                            0.0045                                                                            70  3.25                                        2  50  2000                                                                              1.0 0.905                                                                             43.05                                                                            0.0379                                                                            0.0547                                                                            41  3.0                                         3  40 40000                                                                              2.0 0.850                                                                             56.8                                                                             0.005                                                                             0.0036                                                                            51  3.25                                        4  40 40000                                                                              1.0 0.970                                                                             50.0                                                                             0.0022                                                                            0.0032                                                                            50  3.5                                         5  50 200000                                                                             2.0 .sup. 1.400.sup.b                                                                 40.0                                                                             0.0007                                                                            0.0005                                                                            40  3.0                                         6  50 40000                                                                              2.0 0.858                                                                             42.0                                                                             0.0037                                                                            0.0027                                                                            21  5.75                                        __________________________________________________________________________     .sup.a Mole Ratio                                                             .sup.b After about 50% reaction, chlorination was inhibited.             

Examples 7-13

The general procedure of Example 1 was repeated except that in place ofthe co-catalyst of that example, there were substituted various otherco-catalysts, varying the conditions and amounts of reactants and withthe results as set forth in Table II below.

                                      TABLE II                                    __________________________________________________________________________           Tol/                                                                              FeCl.sub.3                                                         T      Cocat                                                                             Cocat   Wt of Reagents (g)                                                                       Cl.sub.2                                        EX                                                                              Cocat                                                                            °C.                                                                      M.R..sup.a                                                                        M.R..sup.a                                                                        o/p PhMe                                                                             FeCl.sub.3                                                                        Cocat                                                                             SCCM                                                                              Time                                        __________________________________________________________________________     7                                                                              2  50                                                                              40000                                                                             2.0 0.970                                                                             25.0                                                                             0.0022                                                                            0.0017                                                                            25  3.25                                         8                                                                              3  50                                                                              40000                                                                             2.0 0.875                                                                             34.1                                                                             0.003                                                                             0.002                                                                             34  3.25                                         9                                                                              4  50                                                                              40000                                                                             2.0 0.968                                                                             46.6                                                                             0.0041                                                                            0.0034                                                                            48  3.0                                         10                                                                              5  50                                                                              40000                                                                             2.0 .sup. 1.135.sup.b                                                                 45.4                                                                             0.004                                                                             0.0022                                                                            44  3.0                                         11                                                                              6  50                                                                              40000                                                                             2.0 0.827                                                                             48.8                                                                             0.0043                                                                            0.0033                                                                            48  3.0                                         12                                                                              7  50                                                                              40000                                                                             2.0 1.485                                                                             31.8                                                                             0.0028                                                                            0.0025                                                                            32  3.0                                         13                                                                              8  50                                                                              40000                                                                             2.0 0.826                                                                             44.3                                                                             0.0039                                                                            0.003                                                                             43  3.0                                         __________________________________________________________________________     .sup.a Mole Ratio                                                        

Examples 14-17

The general procedure of Example 1 was repeated, substituting equalmolar ratios of co-catalyst Compound 9 in place of co-catalyst 1.Temperature and amounts were varied with the results as shown inExamples 14-17 of Table III, below.

                                      TABLE III                                   __________________________________________________________________________           Tol/                                                                              FeCl.sub.3                                                         T      Cocat                                                                             Cocat   Wt of Reagents (g)                                                                       Cl.sub.2                                        EX                                                                              Cocat                                                                            °C.                                                                      M.R..sup.a                                                                        M.R..sup.a                                                                        o/p PhMe                                                                             FeCl.sub.3                                                                        Cocat                                                                             SCCM                                                                              Time                                        __________________________________________________________________________    14 30                                                                              40000 2.0 .sup. 1.390.sup.b                                                                 32.9                                                                             0.0029                                                                            0.0022                                                                            28  3.0                                         15 40                                                                              40000 2.0 .sup.  0.755.sup.c                                                                64.8                                                                             0.0044                                                                            0.0044                                                                            65  2.5                                         16 50                                                                              40000 2.0 0.813                                                                             55.7                                                                             0.0038                                                                            0.0038                                                                            54  3.0                                         17 60                                                                              40000 2.0 0.906                                                                             52.3                                                                             0.0035                                                                            0.0035                                                                            50  3.0                                         __________________________________________________________________________     .sup.a Mole Ratio                                                             .sup.b Benzyl chloride was a minor product.                                   .sup.c o/p ratio was measured after 30% reaction.                        

Examples 18-20

The general procedure of the preceding examples was repeated,substituting co-catalysts 10, 11, and 12 for the co-catalysts previouslyemployed. In each example the reaction temperature was maintained at 50°C.; the toluene:co-catalyst molar ratio was 4000; and the FeCl₃:co-catalyst molar ratio was 2.0. The amounts of reagents; reactiontime; and o/p ratio obtained are set forth in Table IV below.

                  TABLE IV                                                        ______________________________________                                                 Wt of Reagents (g)                                                                           Cl.sub.2                                              EX  Cocat   o/p    PhMe  FeCl.sub.3                                                                          Cocat  SCCM  Time                              ______________________________________                                        18  10      0.850  52.3  0.0046                                                                              0.0035 59     3.75                             19  11      0.932  53.4  0.0047                                                                              0.0038 58    4.01                              20  12      1.029  32.9  0.0029                                                                              0.0025 42    3.5                               ______________________________________                                    

Example 21 Preparation of2,3-Dihydro-2,3-tetramethylene-1,5-benzo-1,4-thioexpan-5-ones(co-catalysts 1, 3, 4, 6, 7, and 8)

    ______________________________________                                         ##STR20##                                                                     ##STR21##                                                                     ##STR22##                                                                    Cocatalyst                                                                           n        R           M.P. (°C.)                                                                     Yield (%)                                 ______________________________________                                        3      0        H           oil     22                                        1      1        H           113.5-114.5                                                                           66                                        4      1        4-Chloro    121-122 20                                        6      1        5-Methyl    145-147 53                                        7      1        4,5-Dimethoxy                                                                             Gum     12                                        8      1        3-Methyl    122-123 13                                        ______________________________________                                    

General Procedure

To a 0.8M solution of the appropriate 2-mercaptobenzoic acid derivativein reagent grade pyridine was added 1.1 mols of cyclopentene oxide orcyclohexene oxide and the mixture was heated at 80° C. for 2 hours.After cooling the reaction mixture to room temperature, pyridine andvolatiles were removed using a water pump followed by vacuum pump (0.1torr). The residual hydroxy acid derivative intermediate was found by GCto be sufficiently pure to take it to the next step.

The intermediate obtained above was taken in toluene so as to obtain a0.3M solution. To this was added a catalytic amount of p-toluenesulfonicacid (PTSA) and the mixture was refluxed for 1 hour using a Dean Starkwater trap. The mixture was then cooled, and water was added. Theorganic layer was separated, washed twice with aq. NaHCO₃ solution,dried with MgSO₄ and concentrated to give the pure lactone product.

Example 22 Preparation of2,3-Dihydro-2,3-tetramethylene-1,5-benzo-1,4-thioexpan-5-ones(co-catalysts 2) ##STR23## Procedure

A solution of 0.181 g (0.774 mmol) of 1 in 2 mL of dry toluene wastreated with 0.156 g (0.387 mmol) of Lawesson's reagent and the mixturewas heated under reflux for 4 days. The reaction mixture was cooled toroom temperature and the toluene was evaporated. The residue was thensubjected to preparative TLC using 95/5 hexanes/ether to afford 0.16 g(83%) of pure thionolactone 2 as a light orange gum.

Example 23 Preparation of Cyclic Urethanes (co-catalysts 9, 10, 11, and12)

    ______________________________________                                         ##STR24##                                                                     ##STR25##                                                                     ##STR26##                                                                    Co-catalyst                                                                              R        Yield (%)  M.P.                                           ______________________________________                                        9          H        30         180-181                                        10         8-methyl 48         212-214 (Dec)                                  11         10-methyl                                                                              50         223-224                                        12         8-chloro 70         223-224                                        ______________________________________                                    

General Procedure

Synthesis of compounds 9-12 were accomplished using either of the twopathways shown in the scheme above. A representative example ofsynthesis using each method is described below.

Method A. Exemplified by synthesis of compound 9

A mixture of 5.09 g (40.6 mmol) of 2-aminothiophenol and 4.39 g (44.7mmol) of cyclohexene oxide in 85 mL pyridine was stirred at 80° C. for 4hours. The reaction mixture was cooled to room temperature, and pyridineand volatiles were removed under 0.1 torr. The brown residue (7.87 g,87% yield) solidified partly upon standing. GC analysis indicated thisintermediate hydroxyacid to be sufficiently pure for furthertransformation.

A solution of 1.03 g (4.6 mmol) of the above hydroxyacid intermediate ina solvent mixture of 40 mL anhydrous diethyl ether and 20 mLdichloromethane was cooled to 0° C. and treated dropwise with a solutionof 0.46 g (1.55 mmol) of triphosgene in 3 mL of anhydrous diethyl etherover 25 minutes. After addition, the ice bath was allowed to warm up toroom temperature and stirred overnight. The reaction mixture was pouredinto 30 mL water and extracted with 60 mL ether. The water layer wasextracted with 50 mL ether and combined ether extracts were washed with3×100 mL saturated NaHCO₃ solution, then with 50 mL water, dried withMgSO₄ and concentrated to give the crude product. Purification by silicagel column chromatography (24 g silica gel, 20/80 hexanes/ether eluent)afforded 0.44 g (30%) of pure 9 as a pale yellow flaky solid; m.p.180-181° C. The material was also characterized by its proton and carbonNMR spectra.

Example 24 Method B. Exemplified By Synthesis of Compound 10

To a solution of 2.62 g (15 mmol) of 2-amino-4-methylthiophenolhydrochloride in 5 mL of ethanol, a solution of 1.47 g (15 mmol) ofcyclohexene oxide and 1.98 g (30 mmol) of KOH (85% assay) in 15 mLethanol was added and the mixture refluxed for 1 hour under nitrogen.From the mixture, 10 mL of ethanol was then evaporated and the residuewas treated with water (20 mL) to precipitate a solid which wasseparated by filtration. After drying at room temperature, the solid wasdissolved in 50 mL of ether and solution filtered through alumina (20 g,activated, acidic, Brockmann I). The eluate was then evaporated andresidue crystallized from hexane to yield 2.75 g (77%) of purehydroxamine intermediate(2-hydroxycyclohexyl-(2-amino-4-methylphenyl)sulfide); m.p. 94°-97° C.

To a solution of 1.18 g (5 mmol) of the above intermediate hydroxyaminein 10 mL of dichloromethane, a solution of 1 mL (10 mmol) oftriethylamine in 5 mL of dichloromethane was added. The mixture wascooled to -3° C. and 1.5 mL (20 mmol) of phosgene was sparged throughthe solution under slow nitrogen flow (<60 cc/min) for 0.5 hours. Thedark blue mixture was allowed to warm to room temperature and leftstirring overnight. The reaction mixture was treated with water, 5%NaHCO₃ aqueous solution, then water again, dried with Na₂ SO₄, andfiltered through alumina. Dichloromethane was evaporated from the eluateto give a solid residue which was crystallized from ethanol to afford0.63 g (48%) of pure product (10) as colorless crystals; m.p. 212°-214°C. (dec). The material was also characterized from its proton and carbonNMR spectra.

We claim:
 1. A compound of the formula ##STR27## wherein Z is: ##STR28##R is Cl, Br, F, C₁ to C₈ alkyl, or C₁ to C₈ alkoxy; X and Y are eachhydrogen, or taken together form a fused cyclopentyl or cyclohexyl ring,or with the proviso that when Z is 1!, X and Y represent a fusedcyclopentyl or cyclohexyl ring; n is 0, 1, or
 2. 2. A compound accordingto claim 1 characterized by the formula: ##STR29##
 3. A compoundaccording to claim 1 characterized by the formula: ##STR30##
 4. Acompound according to claim 1 characterized by the formula: ##STR31## 5.A compound according to claim 1 characterized by the formula: ##STR32##6. A compound according to claim 1 characterized by the formula:##STR33##
 7. A compound according to claim 1 characterized by theformula: ##STR34##